Abstract

Background

Non-alcoholic fatty liver disease (NAFLD) is a continuum of diseases that include
simple steatosis and non-alcoholic steatohepatitis (NASH) ultimately leading to cirrhosis,
hepatocellular carcinoma and end stage liver failure. Currently there is no approved
treatment for NASH. It is known that bile acids not only have physiological roles
in lipid digestion but also have strong hormonal properties. We have synthesized a
novel chenodeoxycholyl-arginine ethyl ester conjugate (CDCArg) for the treatment of
NAFLD.

Methods

Chemical synthesis of CDCArg was performed. Experiments for prevention and treatment
of NAFLD were carried out on C57BL/6 J male mice that were treated with high fat diet
(HFD, 60% calories from fat). CDCArg or cholic acid bile acids were admixture into
the diets. Food consumption, weight gain, liver histology, intraperitoneal glucose
tolerance test, biochemical analysis and blood parameters were assessed at the end
of the experiment after 5 weeks of diet (prevention study) or after 14 weeks of diet
(treatment study). In the treatment study CDCArg was admixture into the diet at weeks
10–14.

Results

In comparison to HFD treated mice, mice treated with HFD supplemented with CDCArg,
showed reduced liver steatosis, reduced body weight and decreased testicular fat and
liver tissue mass. Blood glucose, cholesterol, insulin and leptin levels were also
lower in this group. No evidence of toxicity of CDCArg was recorded. In fact, liver
injury, as evaluated using plasma hepatic enzyme levels, was low in mice treated with
HFD and CDCArg when compared to mice treated with HFD and cholic acid.

Conclusion

CDCArg supplementation protected the liver against HFD-induced NAFLD without any toxic
effects. These results indicate that basic amino acids e.g., L-arginine and bile acids
conjugates may be a potential therapy for NAFLD.